The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome
The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome
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DOI：
10.1172/jci118547
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发表时间：
1996-03-01
影响因子：
15.9
通讯作者：
Bertagna, X
中科院分区：
文献类型：
--
作者：
deKeyzer, Y;Lenne, F;Bertagna, X
异位ACTH分泌发生在高分化和相当惰性的肿瘤中，如支气管类癌，或者相反，在各种类型的侵袭性和低分化神经内分泌肿瘤中。我们使用最近克隆的人类脑下垂体V3加压素受体作为促肾上腺皮质激素表型的替代分子标记来探索这一现象。检测V3受体、促肾上腺皮质激素释放激素(CRH)受体和前阿片黑素皮质素(POMC)基因在垂体源性和非垂体源性肿瘤中的表达。18例ACTH腺瘤中有17例V3受体和ChR受体mRNAs均有表达，6例正常垂体中6例有V3受体表达，6例生长激素或催乳素腺瘤中有3例V3受体信号很弱，CRH受体信号均为阴性。异位ACTH综合征的8个支气管类癌中，有6个的POMC和V3受体信号与分泌ACTH的腺瘤一样高；相反，在8个不分泌ACTH的类癌中，6个没有POMC信号，V3受体信号很弱。Northern印迹分析显示，V3受体在分泌ACTH的支气管类癌和垂体瘤中的大小相同。导致异位ACTH综合征的其他类型的非垂体肿瘤的POMC和V3受体基因表达水平远低于分泌ACTH的支气管性类癌。与V3受体相比，CRH受体mRNA在大多数神经内分泌肿瘤中检测到，无论其POMC状态如何。这些结果表明，V3受体基因的表达参与了促肾上腺皮质激素的表型。POMC基因的异位表达只是促肾上腺皮质激素细胞分化过程的一个方面，与ACTH分泌的支气管类癌密切相关，为这一特殊的ACTH高分泌综合征的药理学研究甚至治疗开辟了新的可能。
Ectopic ACTH secretion occurs in highly differentiated and rather indolent tumors like bronchial carcinoids or, in contrast, in various types of aggressive and poorly differentiated neuroendocrine tumors. We explored this phenomenon using the recently cloned human pituitary V3 vasopressin receptor as an alternate molecular marker of the corticotroph phenotype. Expression of V3 receptor, corticotrophin releasing hormone (CRH) receptor, and proopiomelanocortin (POMC) genes was examined in tumors of pituitary and nonpituitary origin. A comparative RT-PCR approach revealed signals for both V3 receptor and CHR receptor mRNAs in 17 of 18 ACTH-secreting pituitary adenomas, and 6 of 6 normal pituitaries; in six growth hormone- or prolactin-secreting adenomas, a very faint V3 receptor signal was observed in three cases, and CRH receptor signal was undetected in all. Six of eight bronchial carcinoids responsible for the ectopic ACTH syndrome had both POMC and V3 receptor signals as high as those in ACTH-secreting pituitary adenomas; in contrast, no POMC signal and only a very faint V3 receptor signal were detected in six of eight nonsecreting bronchial carcinoids. Northern blot analysis showed V3 receptor mRNA of identical size in ACTH-secreting bronchial carcinoids and pituitary tumors. Other types of nonpituitary tumors responsible for ectopic ACTH syndrome presented much lower levels of both POMC and V3 receptor gene expression than those found in ACTH-secreting bronchial carcinoids. In contrast with the V3 receptor, CRH receptor mRNA was detected in the majority of neuroendocrine tumors irrespective of their POMC status. These results show that expression of the V3 receptor gene participates in the corticotroph phenotype. Its striking association with ACTH-secreting bronchial carcinoids defines a subset of nonpituitary tumors in which ectopic POMC gene expression is but one aspect of a wider process of corticotroph cell differentiation, and opens new possibilities of pharmacological investigations and even manipulations of this peculiar ACTH hypersecretory syndrome.